Co-crystals of lithium benzoate and uses thereof

ABSTRACT

The present disclosure provides co-crystals of a lithium benzoate compound and a co-former compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     Also provided herein are methods of preparing the co-crystals and uses thereof in treating and/or reducing the risk for a neuropsychiatric disorder (e.g., schizophrenia, psychotic disorders, depressive disorders, bipolar disorders, or neurodegenerative disorders).

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application, U.S.Ser. No. 62/349,582, filed Jun. 13, 2016, which is incorporated byreference herein in the entirety.

BACKGROUND OF THE INVENTION

Co-crystals are a homogeneous multicomponent system including at leastone drug substance (i.e., active ingredient) and at least one co-former,which are held together by supramolecular synthons. Pharmaceuticalco-crystals have attracted significant interest due to the co-crystals'contribution to potential advantageous physicochemical properties of thedrug substance, for example, improved solubility, dissolution rate,bioavailability, physical and/or chemical stability, flowability,hygroscopicity, processability, etc.

In co-crystal development, suitable co-formers for making pharmaceuticalco-crystals of a particular drug substance are typically identified byapproaches based on trial and error. Thus, the selection of suitableco-formers for a drug substance and the ratio between the drug substanceand the co-former to produce desirable pharmaceutical co-crystals, aswell as methods for making such, are the main challenges for producingpharmaceutical co-crystals for a particular drug substance.

SUMMARY OF THE INVENTION

The present disclosure is based on, at least in part, the identificationof suitable co-formers (e.g., sorbic acid, trans-cinnamic acid, andnicotinic acid) for making desirable co-crystals of lithium benzoate,suitable ratios between the co-former and lithium benzoate, and thedevelopment of suitable methods for preparing the desirable co-crystalsdescribed herein. Such lithium benzoate co-crystals are expected to showadvantageous properties, including improved properties such asbioavailability and hygroscopicity.

Accordingly, provided herein are co-crystals of a lithium benzoatecompound and a co-former, wherein the co-former is a compound of Formula(I) as described herein, compositions and kits comprising such, methodsof making such, and uses of the co-crystals for treating and/or reducingthe risk for a neuropsychiatric disorder (e.g., schizophrenia, psychoticdisorders, depression, pain, or Alzheimer's disease).

In one aspect, the present disclosure provides a co-crystal of a lithiumbenzoate compound (e.g., lithium benzoate) and a co-former, wherein theco-former is a compound of Formula (I):

in which

L is alkyl, carbocyclyl, C═C, C═C—C—C═C, C≡C, or absent;

A is alkyl, carbocyclyl, aryl, or heteroaryl; and

X═O or N—B, B being H, alkyl, carbocyclyl, aryl, or heteroaryl.

In certain embodiments, a co-former compound of Formula (I) is of theformula:

wherein A is described herein, and n is 0, 1, or 2.

Exemplary co-former compounds of Formula (I) include, but are notlimited to:

(sorbic acid),

(trans-cinnamic acid), or

(nicotinic acid).

In another aspect, the present disclosure provides compositionsincluding one or more of the co-crystals described herein, and acarrier. In certain embodiments, the composition described herein is apharmaceutical composition. In certain embodiments, the compositiondescribed herein is a nutraceutical composition. In certain embodiments,the composition described herein is a health food. In certainembodiments, the composition described herein is a medical food. Any ofthe compositions described herein may include an effective amount of aco-crystal as described herein. An effective amount described herein maybe a therapeutically effective amount or prophylactically effectiveamount.

In yet another aspect, the present disclosure provides methods fortreating and/or reducing the risk for a neuropsychiatric disorder (e.g.,schizophrenia, psychotic disorders, depression, pain, Alzheimer'sdisease, or dementia), the method comprising administering to a subjectin need of the treatment an effective amount of any of the co-crystalsor any of the compositions comprising such as described herein.

A target neuropsychiatric disorder can include, but is not limited to,schizophrenia, psychotic disorders, Alzheimer's disease, dementia, mildcognitive impairment, benign forgetfulness, closed head injury, autisticspectrum disorder, attention deficit hyperactivity disorders, obsessivecompulsive disorder, tic disorders, childhood learning disorders,premenstrual syndrome, depression, bipolar disorder, anxiety disorders,post-traumatic stress disorder, chronic pain, eating disorders,addiction disorders, personality disorders, Parkinson's disorder,Huntington's disorder, or amyotrophic lateral sclerosis.

In any of the treatment methods as described herein, the subject beingtreated can be a mammal (e.g., human or non-human mammal). For example,the subject can be a human patient having or suspected of having atarget disease as described herein.

Another aspect of the present disclosure relates to kits comprising acontainer in which a co-crystal, or composition thereof, as describedherein, is placed. The kits described herein may include a single doseor multiple doses of the co-crystal or composition. The kits may beuseful in a method of the disclosure. In certain embodiments, the kitfurther includes instructions for using the co-crystal or composition.

In yet another aspect, the present disclosure provides co-crystals andcompositions described herein for use in treating and/or reducing therisk for a neuropsychiatric disorder as described herein and/or formanufacturing a medicament for use in treating the target disease.

The details of one or more embodiments of the disclosure are set forthherein. Other features, objects, and advantages of the disclosure willbe apparent from the Detailed Description, the Examples, and the Claims.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” includes both saturated and unsaturated, straightchain (i.e., unbranched), branched, acyclic, cyclic, or polycyclicaliphatic hydrocarbons, which are optionally substituted with one ormore functional groups. As will be appreciated by one of ordinary skillin the art, “aliphatic” is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties. Thus, the term “alkyl” includes straight,branched and cyclic alkyl groups. An analogous convention applies toother generic terms such as “alkenyl”, “alkynyl”, and the like.Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the likeencompass both substituted and unsubstituted groups. In certainembodiments, “lower alkyl” is used to indicate those alkyl groups(cyclic, acyclic, substituted, unsubstituted, branched or unbranched)having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the disclosure contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-10 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-8 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the disclosurecontain 1-4 carbon atoms. Illustrative aliphatic groups thus include,but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, cyclopentyl, —CH₂-cyclopentyl, n-hexyl,sec-hexyl, cyclohexyl, —CH₂-cyclohexyl moieties and the like, whichagain, may bear one or more substituents. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl, and the like.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃). In certain embodiments, the alkyl group is a substituted C₁₋₁₀alkyl (such as substituted C₁₋₆ alkyl, e.g., —CF₃) .

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl. Inan alkenyl group, a C═C double bond for which the stereochemistry is notspecified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3to 10memberednon-aromatic ring system having ring carbon atoms and 1 to 4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

A “lithium benzoate compound” refers to a compound of the formula:

wherein R¹ is hydrogen, C₁₋₃ alkyl, halogen, —CN, —NO₂, —N₃,C₂₋₄alkenyl, C₂₋₄alkynyl, —OR, —NH₂, or —SR, R being hydrogen, halogen,—CN, —NO₂, —N₃, acyl, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl; and abeing 0, 1, 2, 3, 4, or 5. In certain embodiments, the lithium benzoatecompound is

(lithium benzoate).

“Aralkyl” is a subset of alkyl and aryl and refers to an optionallysubstituted alkyl group substituted by an optionally substituted arylgroup. In certain embodiments, the aralkyl is optionally substitutedbenzyl. In certain embodiments, the aralkyl is benzyl. In certainembodiments, the aralkyl is optionally substituted phenethyl. In certainembodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Unsaturated” or “partially unsaturated” refers to a group that includesat least one double or triple bond. A “partially unsaturated” ringsystem is further intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl groups). Likewise, “saturated” refers to a group that doesnot contain a double or triple bond, i.e., contains all single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, which are divalent bridging groups, are further referred tousing the suffix -ene, e.g., alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted orsubstituted, as valency permits, unless otherwise provided expressly.The term “optionally substituted” refers to substituted orunsubstituted.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionallysubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted”or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present disclosurecontemplates any and all such combinations in order to arrive at astable compound. For purposes of this disclosure, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety. In certain embodiments, thesubstituent is a carbon atom substituent. In certain embodiments, thesubstituent is a nitrogen atom substituent. In certain embodiments, thesubstituent is an oxygen atom substituent. In certain embodiments, thesubstituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa),—SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa), —S(═O)R^(aa),—OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂,—C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa), —SC(═O)SR^(aa),—OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂, —NR^(bb)P(═O)(R^(aa))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂,—P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄,—P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻, —OP(OR^(cc))₂,—OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;wherein X⁻ is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;wherein X⁻ is a counterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S; wherein X⁻ is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl), —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, and a carborane anion(e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplary counterions which may bemultivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻, B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻,carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate,malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate,azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and thelike), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of —C(50O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(aa) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups attached to a nitrogen atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc), and R^(dd) are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl groups,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd)are as defined herein. Nitrogen protecting groups are well known in theart and include those described in detail in Protecting Groups inOrganic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, JohnWiley & Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate,ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc),4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate(Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate(hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate(DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate,alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate(Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tritbutylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethyl sulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N-(N′,N′-dimethylaminomethylene)amine, N,N′isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

Exemplary oxygen atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(c))₃ ⁺X⁻,—P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻, —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and

—P(═O)(N(R^(bb))₂)₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are asdefined herein. In certain embodiments, the oxygen atom substituentpresent on an oxygen atom is an oxygen protecting group (also referredto as a hydroxyl protecting group). Oxygen protecting groups are wellknown in the art and include those described in detail in ProtectingGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd)edition, John Wiley & Sons, 1999, incorporated herein by reference.Exemplary oxygen protecting groups include, but are not limited to,methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM),methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference.

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid, or malonic acidor by using other methods known in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO),tetrahydrofuran (THF), diethyl ether, and the like. The compoundsdescribed herein may be prepared, e.g., in crystalline form, and may besolvated. Suitable solvates include pharmaceutically acceptable solvatesand further include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances, the solvate will be capable ofisolation, for example, when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Representativesolvates include hydrates, ethanolates, and methanolates.

The term “crystalline” or “crystalline form” refers to a solid formsubstantially exhibiting three-dimensional order. In certainembodiments, a crystalline form of a solid is a solid form that issubstantially not amorphous. In certain embodiments, the X-ray powderdiffraction (XRPD) pattern of a crystalline form includes one or moresharply defined peaks.

The term “amorphous” or “amorphous form” refers to a form of a solid(“solid form”), the form substantially lacking three-dimensional order.In certain embodiments, an amorphous form of a solid is a solid formthat is substantially not crystalline. In certain embodiments, the X-raypowder diffraction (XRPD) pattern of an amorphous form includes a widescattering band with a peak at 2θ of, e.g., between 20 and 70°,inclusive, using CuKα radiation. In certain embodiments, the XRPDpattern of an amorphous form further includes one or more peaksattributed to crystalline structures. In certain embodiments, themaximum intensity of any one of the one or more peaks attributed tocrystalline structures observed at a 2θ of between 20 and 70°,inclusive, is not more than 300-fold, not more than 100-fold, not morethan 30-fold, not more than 10-fold, or not more than 3-fold of themaximum intensity of the wide scattering band. In certain embodiments,the XRPD pattern of an amorphous form includes no peaks attributed tocrystalline structures.

The term “co-crystal” refers to a crystalline structure comprising atleast two different components (e.g.,lithium benzoate and a co-former),wherein each of the components is independently an atom, ion, ormolecule. In certain embodiments, none of the components is a solvent.In certain embodiments, at least one of the components is a solvent. Aco-crystal of lithium benzoate and a co-former is different from a saltformed from lithium benzoate and the co-former. In the salt, lithiumbenzoate is complexed with the co-former in a way that proton transfer(e.g., a complete proton transfer) from the co-former to lithiumbenzoate easily occurs at room temperature. In the co-crystal, however,lithium benzoate is complexed with the co-former in a way that protontransfer from the co-former to lithium benzoate does not easily occur atroom temperature. In certain embodiments, in the co-crystal, there is noproton transfer from the co-former to lithium benzoate. In certainembodiments, in the co-crystal, there is partial proton transfer fromthe co-former to lithium benzoate. Co-crystals may be useful to improvethe properties (e.g., solubility, stability, ease of formulation, orbioavailability) of lithium benzoate.

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof) in a particular crystal packingarrangement. All polymorphs have the same elemental composition.Different crystalline forms usually have different X-ray diffractionpatterns, infrared spectra, melting points, density, hardness, crystalshape, optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Variouspolymorphs of a compound can be prepared by crystallization underdifferent conditions.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

The terms “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a co-crystal to reduce, slow, halt or prevent activity ofa particular biological process in a cell relative to vehicle.

When a co-crystal, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively” bindinga first protein, the co-crystal binds the first protein with a higherbinding affinity (e.g., not less than about 2-fold, not less than about5-fold, not less than about 10-fold, not less than about 30-fold, notless than about 100-fold, not less than about 1,000-fold, or not lessthan about 10,000-fold) than binding a second protein or that isdifferent from the first protein. When a co-crystal is referred to as“selectively,” “specifically,” or “competitively” modulating (e.g.,increasing or inhibiting) the activity of a protein, the co-crystalmodulates the activity of the protein to a greater extent (e.g., notless than about 2-fold, not less than about 5-fold, not less than about10-fold, not less than about 30-fold, not less than about 100-fold, notless than about 1,000-fold, or not less than about 10,000-fold) than theactivity of at least one protein that is different from the firstprotein.

The term “aberrant activity” refers to activity deviating from normalactivity. The term “increased activity” refers to activity higher thannormal activity.

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middleaged adult, or senior adult)) or non-human animal. A “patient”refers to a human subject in need of treatment of a disease.

The terms “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a co-crystal described herein, or a composition thereof, inor on a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen) to delay or prevent disease occurrence.Treatment may also be continued after symptoms have resolved, forexample, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a co-crystal described herein refers to anamount sufficient to elicit the desired biological response, i.e.,treating and/or reducing the risk of the condition. As will beappreciated by those of ordinary skill in this art, the effective amountof a co-crystal described herein may vary depending on such factors asthe desired biological endpoint, the pharmacokinetics of the co-crystal,the condition being treated, the mode of administration, and the age andhealth of the subject. In certain embodiments, an effective amount is atherapeutically effective amount. In certain embodiments, an effectiveamount is a prophylactic treatment. In certain embodiments, an effectiveamount is the amount of a co-crystal described herein in a single dose.In certain embodiments, an effective amount is the combined amounts of aco-crystal described herein in multiple doses.

A “therapeutically effective amount” of a co-crystal described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a co-crystalmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent.

A “prophylactically effective amount” of a co-crystal described hereinis an amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a co-crystal means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

The term “neurological disease” refers to any disease of the nervoussystem, including diseases that involve the central nervous system(brain, brainstem, spinal cord, and cerebellum), the peripheral nervoussystem (including cranial nerves), and the autonomic nervous system(parts of which are located in both central and peripheral nervoussystem). Neurodegenerative diseases refer to a type of neurologicaldisease marked by the loss of nerve cells, including, but not limitedto, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, tauopathies (including frontotemporal dementia), multiplesystem atrophy, and Huntington's disease. Examples of neurologicaldiseases include, but are not limited to, headache, stupor and coma,dementia, seizure, sleep disorders, trauma, infections, neoplasms,neuro-ophthalmopathy, movement disorders, demyelinating diseases, spinalcord disorders, and disorders of peripheral nerves, muscle andneuromuscular junctions. Addiction and mental illness, include, but arenot limited to, bipolar disorder and schizophrenia, are also included inthe definition of neurological diseases. Further examples ofneurological diseases include acquired epileptiform aphasia; acutedisseminated encephalomyelitis; adrenoleukodystrophy; agenesis of thecorpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers'disease; alternating hemiplegia; Alzheimer's disease; amyotrophiclateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia;aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiarimalformation; arteriovenous malformation; Asperger syndrome; ataxiatelangiectasia; attention deficit hyperactivity disorder; autism;autonomic dysfunction; back pain; Batten disease; Behcet's disease;Bell's palsy; benign essential blepharospasm; benign focal amyotrophy;benign intracranial hypertension; Binswanger's disease; blepharospasm;Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; braininjury; brain tumors (including glioblastoma multiforme); spinal cordtumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome(CTS); causalgia; central pain syndrome; central pontine myelinolysis;cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis;cerebral atrophy; cerebral gigantism; cerebral palsy;Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy andneuropathic pain; Chiari malformation; chorea; chronic inflammatorydemyelinating polyneuropathy (CIDP); chronic pain; chronic regional painsyndrome; Coffin Lowry syndrome; coma, including persistent vegetativestate; congenital facial diplegia; corticobasal degeneration; cranialarteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulativetrauma disorders; Cushing's syndrome; cytomegalic inclusion body disease(CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome;Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy;diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; earlyinfantile epileptic encephalopathy; empty sella syndrome; encephalitis;encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy;essential tremor; Fabry's disease; Fahr's syndrome; fainting; familialspastic paralysis; febrile seizures; Fisher syndrome; Friedreich'sataxia; frontotemporal dementia and other “tauopathies”; Gaucher'sdisease; Gerstmann's syndrome; giant cell arteritis; giant cellinclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome;HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury;headache; hemifacial spasm; hereditary spastic paraplegia; heredopathiaatactica polyneuritiformis; herpes zoster oticus; herpes zoster;Hirayama syndrome; HIV-associated dementia and neuropathy (see alsoneurological manifestations of AIDS); holoprosencephaly; Huntington'sdisease and other polyglutamine repeat diseases; hydranencephaly;hydrocephalus; hypercortisolism; hypoxia; immune-mediatedencephalomyelitis; inclusion body myositis; incontinentia pigmenti;infantile; phytanic acid storage disease; Infantile Refsum disease;infantile spasms; inflammatory myopathy; intracranial cyst; intracranialhypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease;Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease;Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eatonmyasthenic syndrome; Landau-Kleffner syndrome; lateral medullary(Wallenberg) syndrome; learning disabilities; Leigh's disease;Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy bodydementia; lissencephaly; locked-in syndrome; Lou Gehrig's disease (akamotor neuron disease or amyotrophic lateral sclerosis); lumbar discdisease; lyme disease-neurological sequelae; Machado-Joseph disease;macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieresdisease; meningitis; Menkes disease; metachromatic leukodystrophy;microcephaly; migraine; Miller Fisher syndrome; mini-strokes;mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motorneurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarctdementia; multifocal motor neuropathy; multiple sclerosis and otherdemyelinating disorders; multiple system atrophy with posturalhypotension; muscular dystrophy; myasthenia gravis; myelinoclasticdiffuse sclerosis; myoclonic encephalopathy of infants; myoclonus;myopathy; myotonia congenital; narcolepsy; neurofibromatosis;neuroleptic malignant syndrome; neurological manifestations of AIDS;neurological sequelae of lupus; neuromyotonia; neuronal ceroidlipofuscinosis; neuronal migration disorders; Niemann-Pick disease;O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinaldysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy;opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overusesyndrome; paresthesia; Parkinson's disease; paramyotonia congenita;paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome;Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy;painful neuropathy and neuropathic pain; persistent vegetative state;pervasive developmental disorders; photic sneeze reflex; phytanic acidstorage disease; Pick's disease; pinched nerve; pituitary tumors;polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia(PHN); postinfectious encephalomyelitis; postural hypotension;Prader-Willi syndrome; primary lateral sclerosis; prion diseases;progressive; hemifacial atrophy; progressive multifocalleukoencephalopathy; progressive sclerosing poliodystrophy; progressivesupranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type Iand Type II); Rasmussen's Encephalitis; reflex sympathetic dystrophysyndrome; Refsum disease; repetitive motion disorders; repetitive stressinjuries; restless legs syndrome; retrovirus-associated myelopathy; Rettsyndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease;Schilder's disease; schizencephaly; septo-optic dysplasia; shaken babysyndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleepapnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury;spinal cord tumors; spinal muscular atrophy; stiff-person syndrome;stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis;subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy;sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachsdisease; temporal arteritis; tethered spinal cord syndrome; Thomsendisease; thoracic outlet syndrome; tic douloureux; Todd's paralysis;Tourette syndrome; transient ischemic attack; transmissible spongiformencephalopathies; transverse myelitis; traumatic brain injury; tremor;trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis;vascular dementia (multi-infarct dementia); vasculitis includingtemporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg'ssyndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williamssyndrome; Wilson's disease; and Zellweger syndrome.

The term “psychiatric disorder” refers to mental disorders and includesdiseases and disorders listed in the Diagnostic and Statistical Manualof Mental Disorders—Fourth Edition and Fifth Edition (DSM-IV, DSM-V),published by the American Psychiatric Association, Washington D.C.(1994, 2015). Psychiatric disorders include, but are not limited to,anxiety disorders (e.g., acute stress disorder agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic disorder,posttraumatic stress disorder, separation anxiety disorder, socialphobia, and specific phobia), childhood disorders, (e.g.,attention-deficit/hyperactivity disorder, conduct disorder, andoppositional defiant disorder), eating disorders (e.g., anorexia nervosaand bulimia nervosa), mood disorders (e.g., depression, bipolar disorderI and II, cyclothymic disorder, dysthymic disorder, and major depressivedisorder), personality disorders (e.g., antisocial personality disorder,avoidant personality disorder, borderline personality disorder,dependent personality disorder, histrionic personality disorder,narcissistic personality disorder, obsessive-compulsive personalitydisorder, paranoid personality disorder, schizoid personality disorder,and schizotypal personality disorder), psychotic disorders (e.g., briefpsychotic disorder, delusional disorder, schizoaffective disorder,schizophreniform disorder, schizophrenia, and shared psychoticdisorder), substance-related disorders (e.g., alcohol dependence orabuse, amphetamine dependence or abuse, cannabis dependence or abuse,cocaine dependence or abuse, hallucinogen dependence or abuse, inhalantdependence or abuse, nicotine dependence or abuse, opioid dependence orabuse, phencyclidine dependence or abuse, and sedative dependence orabuse), adjustment disorders, autism, Asperger's disorder, delirium,dementia, multi-infarct dementia, learning and memory disorders (e.g.,amnesia and age-related memory loss), and Tourette's disorder.

The term “neuropsychiatric disorder,” including either neurologicaldiseases or psychiatric disorders, or refers to a disorder that involveseither psychiatric symptoms or syndromes caused by organic braindisorders. The main characteristics of neuropsychiatric symptoms includeoccurrence of the various psychiatric symptoms, cognitive impairment,neurological symptoms or the possibility of early cerebral developmentsymptoms.

The terms “health food” or “health food product” refers to any kind ofliquid and solid/semi-solid materials that are used for nourishinghumans and animals, for improving basic behavioral functioning,hyperactivity, anxiety, depression, sensorimotor gating, pain threshold,memory and/or cognitive functioning, body weight or for facilitatingtreatment of any of the target diseases noted herein. The term“nutraceutical composition” refers to compositions containing componentsfrom food sources and conferring extra health benefits in addition tothe basic nutritional value found in foods.

The term “medical food product” refers to a food product formulated tobe consumed or administered enterally, including a food product that isusually used under the supervision of a physician for the specificdietary management of a target disease, such as those described herein.A “medical food product” composition may refer to a composition that isspecially formulated and processed (as opposed to a naturally occurringfoodstuff used in a natural state) for a patient in need of thetreatment (e.g., human patients who suffer from illness or who requiresuse of the product as a major active agent for alleviating a disease orcondition via specific dietary management). The term “nutraceuticalcomposition” refers to compositions containing components from foodsources and conferring extra health benefits in addition to the basicnutritional value found in foods.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows¹H-NMR of lithium benzoate:sorbic acid (1:2 co-crystal) fromExample 1.

FIG. 2 shows the X-ray powder diffraction (XRPD)of lithiumbenzoate:sorbic acid (1:2 co-crystal) from Example 1, with peaks) (°)of: 6.0; 6.7; 11.0; 11.4; 13.0; 13.3; 16.1; 16.7; 17.5; 18.2; 18.5;20.5; 21.2; 22.4; 22.8; 23.5; 24.2; 24.8; 25.2; 26.8; 27.8.

FIG. 3 shows the Thermogravimetric Analysis (TGA) of lithiumbenzoate:sorbic acid (1:2 co-crystal) from Example 1.

FIG. 4 shows the IR of lithium benzoate:sorbic acid (1:2 co-crystal)(top tracing) vs. lithium benzoate (middle tracing) and sorbic acid (lowtracing) from Example 1.

FIG. 5 shows the ¹H-NMR of lithium benzoate:trans-cinnamic acid (1:1co-crystal) from Example 2.

FIG. 6 shows the XRPD of lithium benzoate:trans-cinnamic acid (1:1co-crystal) from Example 2, with peaks (°) of: 5.2; 7.1; 7.5; 8.0; 10.2;12.8; 13.9; 14.5; 16.2; 17.2; 17.6; 18.5; 20.7; 21.2; 22.1; 23.0; 23.8;24.7; 25.4; 25.8; 26.6; 27.2; 27.8; 29.1; 30.1; 30.9; 31.3; 33.6.

FIG. 7 shows the TGA of lithium benzoate:trans-cinnamic acid (1:1co-crystal) from Example 2.

FIG. 8 shows the melting point, determined using the differentialscanning calorimeter (DSC) method, of lithium benzoate:trans-cinnamicacid (1:1 co-crystal) from Example 2.

FIG. 9 shows the IR of lithium benzoate:trans-cinnamic acid (1:1co-crystalI) (top tracing) vs. lithium benzoate (middle tracing) andtrans-cinnamic acid (low tracing) from Example 2.

FIG. 10 shows the ¹H-NMR of lithium benzoate:nicotinic acid (1:1co-crystal) from Example 3.

FIG. 11 shows the XRPD of lithium benzoate:nicotinic acid (1:1co-crystal) from Example 3, with peaks) (°) of: 6.5; 11.1; 13.1; 15.5;16.7; 17.5; 18.4; 19.7; 20.3; 20.7; 21.2; 21.6; 22.3; 22.8; 24.4; 24.8;25.9; 26.9; 28.0; 28.7; 29.2; 30.0; 30.6; 31.6; 32.3; 33.6; 34.1; 35.8;36.3; 37.2; 38.3; 39.1; 39.9; 41.2; 41.8; 42.8.

FIG. 12 shows the TGA of lithium benzoate:nicotinic acid (1:1co-crystal) from Example 3.

FIG. 13 shows the IR of lithium benzoate:nicotinic acid (1:1 co-crystal)(top tracing) vs. lithium benzoate (middle tracing) and nicotinic acid(low tracing) from Example 3.

DETAILED DESCRIPTION

The present disclosure provides co-crystals of a lithium benzoatecompound such as lithium benzoate and a co-former, which is a compoundof Formula (I) as described herein. Such co-crystals are expected topossess advantageous physical, chemical, physiologic, and/or therapeuticfeatures as relative to the lithium benzoate compound in non-co-crystalform or in different co-crystal form. For example, the lithium benzoateco-crystals are expected to show advantageous properties, includingimproved solubility, dissolution rate, physical stability, chemicalstability, processability, bioavailability, and superior pharmacokineticor therapeutic properties. The co-crystals are useful in treating and/orreducing the risk for various diseases and disorders, includingneuropsychiatric disorders in a subject. Thus, also provided herein aremethods of preparing the co-crystals, compositions, kits, and methods ofusing the co-crystals described herein for treating and/or reducing therisk for any of the target diseases described herein.

Co-Crystals of Lithium Benzoate and Co-Former

One aspect of the present disclosure relates to the co-crystals of alithium benzoate compound and a co-former as described herein, as wellas their hydrates, polymorphs, tautomers, stereoisomers, isotopicallylabeled derivatives, or prodrugs. These co-crystals are useful intreating and/or reducing the risk for neuropsychiatric disorders in asubject.

In certain embodiments, a co-crystal described herein is a co-crystal ofa lithium benzoate compound such as lithium benzoate and a co-former,wherein the co-former is a compound of Formula (I):

in which A, L, and X are as described herein, or a solvate, hydrate,polymorph, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In Formula (I), in some embodiments, A can be alkyl. In someembodiments, A can be substituted or unsubstituted C₁₋₆ alkyl (e.g.,methyl, ethyl, or propyl). In some embodiments, A can be methyl. In someembodiments, A can be ethyl. In some embodiments, A can be propyl. Insome embodiments, A can be substituted or unsubstituted carbocyclyl(e.g., substituted or unsubstituted, 3- to 7-membered, monocycliccarbocyclyl comprising zero, one, or two double bonds in the carbocyclicring system). In some embodiments, A can be substituted or unsubstitutedaryl (e.g., phenyl or benzyl). In some embodiments, A can be substitutedor unsubstituted phenyl. In some embodiments, A can be phenyl. In someembodiments, A can be substituted or unsubstituted 5- to 7-memberedmonocyclic heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring system are independently nitrogen, oxygen, or sulfur. Insome embodiments, A can be pyridine.

In Formula (I), in some embodiments, L can be alkyl. In someembodiments, L can be substituted or unsubstituted C₁₋₆ alkyl (e.g.,methyl, ethyl, or propyl). In some embodiments, L can be methyl. In someembodiments, L can be ethyl. In some embodiments, L can be propyl. Insome embodiments, L can be substituted or unsubstituted carbocyclyl(e.g., substituted or unsubstituted, 3- to 7-membered, monocycliccarbocyclyl comprising zero, one, or two double bonds in the carbocyclicring system). In some embodiments, L can be C═C. In some embodiments, Lcan be C═C—C═C. In some embodiments, L can be C≡C. In some embodiments,L can be absent.

In some embodiments, X can be O. In some embodiments, X can be —N(B),wherein B is H, alkyl, carbocyclyl, aryl, or heteroaryl. In someembodiments, X can be —NH. In some embodiments, X can be —N(alkyl)(e.g., —N(substituted or unsubstituted C₁₋ ₆ alkyl)). In someembodiments, X can be —N(methyl). In some embodiments, X can be—N(ethyl). In some embodiments, X can be —N(propyl). In someembodiments, X can be —N(carbocyclyl) (e.g., —N(substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system)). In someembodiments, X can be —N(aryl) (e.g., —N(substituted or unsubstitutedaryl)). In some embodiments, X can be —N(phenyl). In some embodiments, Xcan be —N(benzyl). In some embodiments, X can be —N(heteroaryl) (e.g.,—N(substituted or unsubstituted 5- to 7-membered monocyclic heteroaryl,wherein one, two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur)).

In some embodiments, L can be C═C and A can be C₁-C₆ alkyl(e.g., methyl,ethyl, or propyl). In some embodiments, L can be C═C and A can be aryl.In some embodiments, L can be C═C and A can be heteroaryl (e.g.,substituted or unsubstituted 5- to 7-membered monocyclic heteroaryl,wherein one, two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In some embodiments, L canbe C═C—C═C and A can be C₁-C₆ alkyl(e.g., methyl, ethyl, or propyl). Insome embodiments, L can be C═C—C═C and A can be aryl. In someembodiments, L can be C═C—C═C and A can be heteroaryl (e.g., substitutedor unsubstituted 5- to 7-membered monocyclic heteroaryl, wherein one,two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur).

In some embodiments, L can be C═C—C═C, A can be methyl, and X can be O.In some embodiments, L can be C═C, A can be phenyl, and X can be O. Lcan be absent, A can be pyridyl, and X can be O.

In some embodiments, a co-former compound of Formula (I) is of theformula:

wherein A is described herein, and n is 0, 1, or 2. In some embodiments,n is 0. In some embodiments, the co-former compound is of the formula:

(e.g., nicotinic acid). In some embodiments, n is 1. In someembodiments, the co-former compound is of the formula:

(e.g., trans-cinnamic acid). In some embodiments, n is 2. In someembodiments, the co-former compound is of the formula:

(e.g., sorbic acid).

In some embodiments, the lithium benzoate and the co-former can exist inthe co-crystal in a molecular ratio ranging from 1:10 to 10:1. In someembodiments, the lithium benzoate and the co-former can exist in theco-crystal in a molecular ratio ranging from 1:5 to 5:1. In someembodiments, the lithium benzoate and the co-former can exist in theco-crystal in a molecular ratio ranging from 1:3 to 3:1. In someembodiments, the lithium benzoate and the co-former can exist in theco-crystal in a molecular ratio ranging from 1:2 to 2:1. In someembodiments, the lithium benzoate and the co-former can exist in theco-crystal in a molecular ratio of 1:2. In some embodiments, the lithiumbenzoate and the sorbic acid co-former can exist in a molecular ratio of1:1. In some embodiments, the lithium benzoate and the sorbic acidco-former can exist in a molecular ratio of 1:2. In some embodiments,the lithium benzoate and the trans-cinnamic acid co-former can exist inthe co-crystal in a molecular ratio of 1:2. In some embodiments, thelithium benzoate and the nicotinic acid co-former can exist in theco-crystal in a molecular ratio of 1:2. In some embodiments, the lithiumbenzoate and the co-former can exist in the co-crystal in a molecularratio of 1:1. In some embodiments, the lithium benzoate and thetrans-cinnamic acid co-former can exist in the co-crystal in a molecularratio of 1:1. In some embodiments, the lithium benzoate and thenicotinic acid co-former can exist in the co-crystal in a molecularratio of 1:1. In some embodiments, the lithium benzoate and the sorbicacid co-former can exist in a molecular ratio of 1:1.

In some embodiments, the co-crystal has a powder X-ray diffractionpattern substantially as depicted in FIG. 2. In some embodiments, theco-crystal has powder X-ray diffraction pattern substantially asdepicted in FIG. 6, and an endothermic peak corresponding to the meltingpoint of about 188° C. In some embodiments, the endothermic peakcorresponds to the melting point of about 180° C. In some embodiments,the co-crystal has a powder X-ray diffraction pattern substantially asdepicted in FIG. 6. In some embodiments, the co-crystal has a powderX-ray diffraction pattern substantially as depicted in FIG. 12, and anendothermic peak corresponding to the melting point of about 161° C. Insome embodiments, the endothermic peak corresponds to the melting pointof about 160° C. In some embodiments, the co-crystal has a powder X-raydiffraction pattern substantially as depicted in FIG. 12.

Method of Synthesis

The co-crystals described herein can be prepared by any of the methodsdescribed herein. Below are some examples.

In certain embodiments, the synthesis of a co-crystal of lithiumbenzoate and a co-former compound of Formula (I) includes a first stepof mixing lithium benzoate and a co-former of Formula (I), followed by astep of heating and stirring the solution, and a step of collecting theformed co-crystal. In certain embodiments, the first step in thesynthesis of a co-crystal of lithium benzoate and a co-former compoundof Formula (I) is a step of mixing lithium benzoate and the co-formerata temperature of about 40-110° C. to form a saturated solution, whereinthe lithium benzoate and the co-former are at a molar ratio of 1:10 to10:1. In certain embodiments, the lithium benzoate and the co-former aremixed at a temperature of 40-50° C. to form a saturated solution. Incertain embodiments, the lithium benzoate and the co-former are mixed ata temperature of 40-60° C. to form a saturated solution. In certainembodiments, the lithium benzoate and the co-former are mixed at atemperature of 40-80° C. to form a saturated solution. In certainembodiments, the lithium benzoate and the co-former are mixed at atemperature of 40-100° C. to form a saturated solution. In certainembodiments, the lithium benzoate and the co-former are mixed at atemperature of 50-110° C. to form a saturated solution. In certainembodiments, the lithium benzoate and the co-former are mixed at atemperature of 50-100° C. to form a saturated solution. In certainembodiments, the lithium benzoate and the co-former are mixed at atemperature of 60-110° C. to form a saturated solution. In certainembodiments, the lithium benzoate and the co-former are mixed at atemperature of 80-110° C. to form a saturated solution. In certainembodiments, the lithium benzoate and the co-former are mixed at atemperature of 100-110° C. to form a saturated solution. In someembodiments, the lithium benzoate and the co-former are in a molecularratio ranging from 1:5 to 5:1. In some embodiments, the lithium benzoateand the co-former are in a molecular ratio ranging from 1:3 to 3:1. Insome embodiments, the lithium benzoate and the co-former are in amolecular ratio ranging from 1:2 to 2:1. In some embodiments, thelithium benzoate and the co-former are in a molecular ratio of 1:2. Insome embodiments, the lithium benzoate and the co-former are in amolecular ratio of 1:1.

In certain embodiments, the second step in the synthesis of a co-crystalof lithium benzoate and a co-former compound of Formula (I) is a step ofheating and stirring the solution at a temperature of about 70-150° C.to allow formation of the co-crystal. In certain embodiments, in thesecond step in the synthesis of a co-crystal, the solution is heated andstirred to a temperature of about 70-125° C. In certain embodiments, inthe second step in the synthesis of a co-crystal, the solution is heatedand stirred to a temperature of about 70-100° C. In certain embodiments,in the second step in the synthesis of a co-crystal, the solution isheated and stirred to a temperature of about 80-150° C. In certainembodiments, in the second step in the synthesis of a co-crystal, thesolution is heated and stirred to a temperature of about 100-150° C. Incertain embodiments, in the second step in the synthesis of aco-crystal, the solution is heated and stirred to a temperature of about125-150° C. In certain embodiments, the third step in the synthesis of aco-crystal of lithium benzoate and a co-former compound of Formula (I)is a step of collecting the co-crystal formed in the second step. Incertain embodiments, the first step is performed by adding the solventin a dropwise manner into the lithium benzoate and co-former andstirring the mixture thus formed to allow dissolution of the lithiumbenzoate and co-former in the solvent.

In certain embodiments, the synthesis of a co-crystal of lithiumbenzoate and a co-former compound of Formula (I) includes a first stepof providing a co-crystal of lithium benzoate and a co-former of Formula(I), followed by a second step of dissolving the co-crystal in a solventat a temperature ranging from about 35-110° C. to form a solution,followed by a third step of stirring the solution at a temperature ofabout 40-110° C. for a first period to allow formation of theco-crystal; wherein the first period is about 1-10 days, and a finalstep of collecting the formed co-crystal. In certain embodiments, thesecond step of dissolving the co-crystal is conducted in a solvent at atemperature ranging from about 40-110° C. to form a solution. In certainembodiments, the second step of dissolving the co-crystal is conductedin a solvent at a temperature ranging from about 60-110° C. to form asolution. In certain embodiments, the second step of dissolving theco-crystal is conducted in a solvent at a temperature ranging from about80-110° C. to form a solution. In certain embodiments, the second stepof dissolving the co-crystal is conducted in a solvent at a temperatureranging from about 35-50° C. to form a solution. In certain embodiments,the second step of dissolving the co-crystal is conducted in a solventat a temperature ranging from about 35-60° C. to form a solution. Incertain embodiments, the second step of dissolving the co-crystal isconducted in a solvent at a temperature ranging from about 35-80° C. toform a solution. In certain embodiments, the third step of stirring thesolution is conducted at a temperature of about 40-110° C. for a firstperiod to allow formation of the co-crystal. In certain embodiments, thethird step of stirring the solution is conducted at a temperature ofabout 40-60° C. for a first period to allow formation of the co-crystal.In certain embodiments, the third step of stirring the solution isconducted at a temperature of about 40-80° C. for a first period toallow formation of the co-crystal. In certain embodiments, the thirdstep of stirring the solution is conducted at a temperature of about40-100° C. for a first period to allow formation of the co-crystal. Incertain embodiments, the third step of stirring the solution isconducted at a temperature of about 50-110° C. for a first period toallow formation of the co-crystal. In certain embodiments, the thirdstep of stirring the solution is conducted at a temperature of about70-110° C. for a first period to allow formation of the co-crystal. Incertain embodiments, the third step of stirring the solution isconducted at a temperature of about 90-110° C. for a first period toallow formation of the co-crystal. In certain embodiments, the thirdstep of stirring the solution is conducted for a first period of 1-10days (e.g., 1-4 days, 1-6 days, 1-8 days, 3-10 days, 4-10 days, 6-10days, or 8-10 days). In certain embodiments, in a four-step synthesis ofa co-crystal of lithium benzoate and a co-former compound of Formula(I), the last step is followed by a step of stirring the solution at atemperature of about 40-110° C. for a second period, wherein the secondperiod is about 1-10 days.

In certain embodiments, the step of stirring the solution for a secondperiod is conducted at a temperature of about 40-110° C. (e.g., 40-60°C., 40-80° C., 40-100° C., 50-100° C., 70-100° C., or 90-100° C.). Incertain embodiments, the step of stirring the solution is for a secondperiod of about 1-10 days (e.g., 1-4 days, 1-6 days, 1-8 days, 3-10days, 4-10 days, 6-10 days, or 8-10 days).

Exemplary methods for preparing the co-crystals described herein areprovided below:

Method 1: Crystallization via Heating in Saturated Solution

In some embodiments, crystallization can be carried out by heating in asaturated solution. Lithium benzoate and a co-former as described hereincan be mixed in a molar ratio of ranging from 1:10 to 10:1 and placed ina round-bottom flask in a water bath at room temperature or elevatedtemperature (e.g., 60-65° C.). The solvent (e.g., methanol, ethanol,etc.) can then be added dropwise via an addition funnel into the flaskand the resulting solution was stirred until all powders were fullydissolved. The mixture thus formed can be heated and stirred at about70-75° C. and the co-crystal started to form. Heating and stirring canbe discontinued when the formation of co-crystal ceases. The solutioncan be allowed to cool to at room temperature and the co-crystal can becollected by suction filtration and washed with the mother liquor ifnecessary before subjecting to drying at room temperature or elevatedtemperature in the oven overnight.

Method 2: Crystallization via Re-dissolving and Heating in SaturatedSolution

In some embodiments, crystallization can be carried out by re-dissolvingand heating in a saturated solution. A co-crystal of lithium benzoateobtained by any methods described here, for example, Method 1 above, andlithium benzoate or the co-crystal former can be mixed in a molar ratioranging from 1:10 to 10:1 and re-dissolved in a suitable solvent at roomor elevated temperature (e.g., 40-65° C.). The mixture thus formed canbe stirred at elevated temperature for a certain period of time (e.g.,1-7 days) and the volume of methanol was reduced by evaporation,followed by further stirring for another certain period of time (e.g.,1-3 days). The solution can be allowed to cool to at room temperatureand the co-crystal formed can be collected by suction filtration andwashed with the mother liquor if necessary before subjecting to dryingat room temperature or elevated temperature in the oven overnight.

Compositions

The present disclosure provides compositions comprising a co-crystaldescribed herein and a carrier. In certain embodiments, the carrier is apharmaceutically acceptable excipient. In certain embodiments, acomposition described herein comprises a co-crystal described herein,and a carrier. The compositions described herein are useful in treatingand/or reducing the risk for a neuropsychiatric disorder.

In certain embodiments, the composition is a pharmaceutical composition.In certain embodiments, the composition is a nutraceutical composition.In certain embodiments, the composition is a health food. In someembodiments, the compositions described herein can be a health food orhealth food product, which can be any kinds of liquid andsolid/semi-solid materials that are used for nourishing humans andanimals, for improving basic behavioral functioning, hyperactivity,anxiety, depression, sensorimotor gating, pain threshold, memory and/orcognitive functioning, or for facilitating treatment of any of thetarget diseases noted herein (e.g., a neuropsychiatric disorder,including those described herein). The health food product may be a foodproduct (e.g., tea-based beverages, juice, soft drinks, coffee, milk,jelly, cookies, cereals, chocolates, snack bars, herbal extracts, dairyproducts (e.g., ice cream, and yogurt)), a food/dietary supplement, or anutraceutical formulation.

The health food product described herein, may comprise one or moreedible carriers, which confer one or more of the benefits to the productas described herein. Examples of edible carriers include starch,cyclodextrin, maltodextrin, methylcellulose, carbonmethoxy cellulose,xanthan gum, and aqueous solutions thereof. Other examples includesolvents, dispersion media, coatings, surfactants, antioxidants,preservatives (e.g., antibacterial agents, antifungal agents), isotonicagents, absorption delaying agents, stabilizers, gels, binders,excipients, disintegration agents, lubricants, sweetening agents,flavoring agents, dyes, such like materials and combinations thereof, aswould be known to one of ordinary skill in the art. In some examples,the health food products described herein may further includeneuroprotective foods, such as fish oil, flax seed oil, and/or benzoate.

In some examples, the health food product is a nutraceuticalcomposition, which refers to compositions containing components fromfood sources and conferring extra health benefits in addition to thebasic nutritional value found in foods. A nutraceutical composition asdescribed herein comprises the co-crystal described herein (e.g., thelithium benzoate compound and co-crystal as described herein) andadditional ingredients and supplements that promote good health and/orenhance stability and bioactivity of the co-crystals.

The actions of nutraceutical compositions may be fast or/and short-termor may help achieve long-term health objectives as those describedherein, e.g., improving basic behavioral functioning, hyperactivity,anxiety, depression, sensorimotor gating, pain threshold, memory and/orcognitive functioning in, e.g., human subjects who have or are at riskfor neuropsychiatric disorders. The nutraceutical compositions may becontained in an edible material, for example, as a dietary supplement ora pharmaceutical formulation. As a dietary supplement, additionalnutrients, such as vitamins, minerals or amino acids may be included.The composition can also be a drink or a food product, e.g., tea, softdrink, juice, milk, coffee, cookie, cereal, chocolate, and snack bar. Ifdesired, the composition can be sweetened by adding a sweetener such assorbitol, maltitol, hydrogenated glucose syrup and hydrogenated starchhydrolyzate, high fructose corn syrup, cane sugar, beet sugar, pectin,or sucralose.

The nutraceutical composition disclosed herein can be in the form of asolution. For example, the nutraceutical formulation can be provided ina medium, such as a buffer, a solvent, a diluent, an inert carrier, anoil, or a creme. In some examples, the formulation is present in anaqueous solution that optionally contains a non-aqueous co-solvent, suchas an alcohol. The nutraceutical composition can also be in the form ofpowder, paste, jelly, capsule, or tablet. Lactose and corn starch arecommonly used as diluents for capsules and as carriers for tablets.Lubricating agents, such as magnesium stearate, are typically added toform tablets.

The health food products may be formulated for a suitable administrationroute, for example, oral administration. For oral administration, thecomposition can take the form of, for example, tablets or capsules,prepared by conventional means with acceptable excipients such asbinding agents (for example, pregelatinised maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (forexample, lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (for example, magnesium stearate, talc orsilica); disintegrants (for example, potato starch or sodium starchglycolate); or wetting agents (for example, sodium lauryl sulphate). Thetablets can be coated by methods well known in the art. Also includedare bars and other chewable formulations.

In some examples, the health food product can be in a liquid form andthe one or more edible carriers can be a solvent or dispersion mediumcomprising but not limited to, ethanol, polyol (e.g., glycerol,propylene glycol, liquid polyethylene glycol), lipids (e.g.,triglycerides, vegetable oils, liposomes) or combinations thereof. Theproper fluidity can be maintained, for example, by the use of a coating,such as lecithin; by the maintenance of the required particle size bydispersion in carriers such as, for example liquid polyol or lipids; bythe use of surfactants such as, for example hydroxypropylcellulose; orcombinations thereof. In many cases, it will be advisable to include anisotonic agent, such as, for example, sugars, sodium chloride orcombinations thereof.

Liquid preparations for oral administration can take the form of, forexample, solutions, syrups or suspensions, or they can be presented as adry product for constitution with water or other suitable vehicle beforeuse. In one embodiment, the liquid preparations can be formulated foradministration with fruit juice. Such liquid preparations can beprepared by conventional means with pharmaceutically acceptableadditives such as suspending agents (for example, sorbitol syrup,cellulose derivatives or hydrogenated edible fats); emulsifying agents(for example, lecithin or acacia); non-aqueous vehicles (for example,almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (for example, methyl or propyl-p-hydroxybenzoates,benzoate or sorbate). In certain embodiments, the composition is amedical food. A medical food product is a food product formulated to beconsumed or administered enterally. Such a food product is usually usedunder the supervision of a physician for the specific dietary managementof a target disease, such as those described herein. In some instances,such a medical food composition is specially formulated and processed(as opposed to a naturally occurring foodstuff used in a natural state)for a patient in need of the treatment (e.g., human patients who sufferfrom illness or who requires use of the product as a major active agentfor alleviating a disease or condition via specific dietary management).In some examples, a medical food composition described herein is not oneof those that would be simply recommended by a physician as part of anoverall diet to manage the symptoms or reduce the risk of a disease orcondition.

Any of the medical food compositions described herein, comprisinglithium benzoate and a co-former of Formula (I) thereof and at least onecarrier (e.g., those described herein), can be in the form of a liquidsolution; powder, bar, wafer, a suspension in an appropriate liquid orin a suitable emulsion, as detailed below. The at least one carrier,which can be either naturally-occurring or synthetic (non-naturallyoccurring), would confer one or more benefits to the lithium benzoateand co-former in the composition, for example, stability,bioavailability, and/or bioactivity. Any of the carriers describedherein may be used for making the medical food composition. In someembodiments, the medical food composition may further comprise one ormore additional ingredients selected from the group including, but notlimited to natural flavors, artificial flavors, major trace andultra-trace minerals, minerals, vitamins, oats, nuts, spices, milk, egg,salt, flour, lecithin, xanthan gum and/or sweetening agents. The medicalfood composition may be placed in a suitable container, which mayfurther comprise at least an additional therapeutic agent such as thosedescribed herein.

In certain embodiments, the co-crystal described herein is provided inan effective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount(e.g., amount effective for treating and/or reducing the risk for aneuropsychiatric disorder). In certain embodiments, the neuropsychiatricdisorder is a neurological disorder, e.g., Alzheimer's disease. Incertain embodiments, the effective amount is a prophylacticallyeffective amount (e.g., amount effective for preventing aneuropsychiatric disorder in a subject in need thereof).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include bringing the co-crystal described herein (i.e., the“active ingredient”) into association with a carrier or excipient,and/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping, and/or packaging the product into a desiredsingle- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the digestive tract, optionally, ina delayed manner. Examples of encapsulating agents which can be usedinclude, but are not limited to, polymeric substances and waxes.

Although the descriptions of pharmaceutical compositions provided hereinare mainly directed to pharmaceutical compositions which are suitablefor administration to humans, such compositions are generally suitablefor administration to animals of all sorts. Modification ofpharmaceutical compositions suitable for administration to humans inorder to render the compositions suitable for administration to variousanimals is well understood, and the ordinarily skilled veterinarypharmacologist can design and/or perform such modification with ordinaryexperimentation.

The co-crystals provided herein are typically formulated in dosage unitform for ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orco-crystal described herein and a container (e.g., a vial, ampule,bottle, syringe, and/or dispenser package, or other suitable container).In some embodiments, provided kits may optionally further include asecond container comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or co-crystal describedherein. In some embodiments, the pharmaceutical composition orco-crystal described herein provided in the first container and thesecond container are combined to form one unit dosage form.

In certain embodiments, a kit described herein includes a firstcontainer comprising a co-crystal or composition described herein. Incertain embodiments, a kit described herein is useful in treating and/orreducing the risk for a neuropsychiatric disorder in a subject in needthereof.

In certain embodiments, a kit described herein further includesinstructions for using the co-crystal or composition included in thekit. A kit described herein may also include information as required bya regulatory agency such as the U.S. Food and Drug Administration (FDA).In certain embodiments, the information included in the kits isprescribing information. In certain embodiments, the kits andinstructions provide for treating and/or reducing the risk for aneuropsychiatric disorder in a subject in need thereof. A kit describedherein may include one or more additional pharmaceutical agentsdescribed herein as a separate composition.

Methods of Treatment

The present disclosure provides methods of treating and/or reducing therisk for a neuropsychiatric disorder, in a subject in need thereof, themethods comprising administering to the subject an effective amount(e.g., therapeutically effective amount) of a co-crystal, or compositionthereof, described herein.

Another aspect of the present disclosure relates to methods ofpreventing a neuropsychiatric disorder in a subject in need thereof, themethods comprising administering to the subject an effective amount(e.g., prophylactically effective amount) of a co-crystal, orcomposition thereof, described herein.

The co-crystals and compositions described herein are useful in treatingand/or preventing neuropsychiatric disorder. In certain embodiments, theneuropsychiatric disorder is schizophrenia. In certain embodiments, theneuropsychiatric disorder is a psychotic disorder. In certainembodiments, the neuropsychiatric disorder is Alzheimer's disease. Incertain embodiments, the neuropsychiatric disorder is dementia. Incertain embodiments, the neuropsychiatric disorder is mild cognitiveimpairment. In certain embodiments, the neuropsychiatric disorder isbenign forgetfulness. In certain embodiments, the neuropsychiatricdisorder is closed head injury. In certain embodiments, theneuropsychiatric disorder is autistic spectrum disorder, includingAsperger's disorder. In certain embodiments, the neuropsychiatricdisorder is a attention deficit hyperactivity disorder. In certainembodiments, the neuropsychiatric disorder is obsessive compulsivedisorder. In certain embodiments, the neuropsychiatric disorder is a ticdisorder. In certain embodiments, the neuropsychiatric disorder is achildhood learning disorder. In certain embodiments, theneuropsychiatric disorder is premenstrual syndrome. In certainembodiments, the neuropsychiatric disorder is depression, includingdysthymia and bereavement. In certain embodiments, the neuropsychiatricdisorder is bipolar disorder including bipolar I and II disorders. Incertain embodiments, the neuropsychiatric disorder is an anxietydisorders including panic and phobic disorders. In certain embodiments,the neuropsychiatric disorder is post-traumatic stress disorder. Incertain embodiments, the neuropsychiatric disorder is chronic pain. Incertain embodiments, the neuropsychiatric disorder is an eating disorderincluding bulimia and anorexia. In certain embodiments, theneuropsychiatric disorder is an addiction disorders including substancedependence or abuse. In certain embodiments, the neuropsychiatricdisorder is a personality disorder. In certain embodiments, theneuropsychiatric disorder is Parkinson's disorder. In certainembodiments, the neuropsychiatric disorder is Huntington's disorder. Incertain embodiments, the neuropsychiatric disorder is amyotrophiclateral sclerosis.

In certain embodiments, the method described herein further includesadministering to the subject an additional pharmaceutical agent. Incertain embodiments, the method described herein further includescontacting the biological sample with an additional pharmaceuticalagent. In certain embodiments, the method described herein furtherincludes contacting the tissue with an additional pharmaceutical agent.In certain embodiments, the method described herein further includescontacting the cell with an additional pharmaceutical agent.

The co-crystals and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, subcutaneous,intradermal, rectal, intravaginal, intraperitoneal, topical (as bypowders, ointments, creams, and/or drops). Specifically contemplatedroutes are oral administration, intravenous administration (e.g.,systemic intravenous injection), regional administration via bloodand/or lymph supply, and/or direct administration to an affected site.In general, the most appropriate route of administration will dependupon a variety of factors including the nature of the agent (e.g., itsstability in the environment of the gastrointestinal tract), and/or thecondition of the subject (e.g., whether the subject is able to tolerateoral administration).

The exact amount of a co-crystal required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular co-crystal, mode of administration,and the like. An effective amount may be included in a single dose(e.g., single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to asubject or applied to a biological sample, tissue, or cell, any twodoses of the multiple doses include different or substantially the sameamounts of a co-crystal described herein. In certain embodiments, whenmultiple doses are administered to a subject or applied to a biologicalsample, tissue, or cell, the frequency of administering the multipledoses to the subject or applying the multiple doses to the tissue orcell is three doses a day, two doses a day, one dose a day, one doseevery other day, one dose every third day, one dose every week, one doseevery other week, one dose monthly or one dose every other month. Incertain embodiments, the frequency of administering the multiple dosesto the subject or applying the multiple doses to the tissue or cell isone dose per day. In certain embodiments, the frequency of administeringthe multiple doses to the subject or applying the multiple doses to thetissue or cell is two doses per day. In certain embodiments, whenmultiple doses are administered to a subject or applied to a biologicalsample, tissue, or cell, the duration between the first dose and lastdose of the multiple doses is one day, two days, four days, one week,two weeks, three weeks, one month, two months, three months, fourmonths, six months, nine months, one year, two years, three years, fouryears, five years, seven years, ten years, fifteen years, twenty years,or the lifetime of the subject, biological sample, tissue, or cell. Incertain embodiments, the duration between the first dose and last doseof the multiple doses is three months, six months, or one year. Incertain embodiments, the duration between the first dose and last doseof the multiple doses is the lifetime of the subject, biological sample,tissue, or cell. In certain embodiments, a dose (e.g., a single dose, orany dose of multiple doses) described herein includes independentlybetween 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg,between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and1,000 mg, or between 1 g and 10 g, inclusive, of a co-crystal describedherein. In certain embodiments, a dose described herein includesindependently between 3 mg and 10 mg, inclusive, of a co-crystaldescribed herein. In certain embodiments, a dose described hereinincludes independently between 10 mg and 30 mg, inclusive, of aco-crystal described herein. In certain embodiments, a dose describedherein includes independently between 30 mg and 100 mg, inclusive, of aco-crystal described herein. In certain embodiments, a dose describedherein includes independently between 100 mg and 300 mg, inclusive, of aco-crystal as described herein. In certain embodiments, a dose describedherein includes independently between 300 mg and 1000 mg, inclusive, ofa co-crystal described herein.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

A co-crystal or composition, as described herein, can be administered incombination with one or more additional pharmaceutical agents (e.g.,therapeutically and/or prophylactically active agents) useful intreating and/or reducing the risk for a neuropsychiatric disorder. Theco-crystals or compositions can be administered in combination withadditional pharmaceutical agents that improve their activity (e.g.,activity (e.g., potency and/or efficacy) in treating and/or reducing therisk for a neuropsychiatric disorder in a subject in need thereof),improve bioavailability, improve safety, reduce drug resistance, reduceand/or modify metabolism, inhibit excretion, and/or modify distributionin a subject, biological sample, tissue, or cell. It will also beappreciated that the therapy employed may achieve a desired effect forthe same disorder, and/or it may achieve different effects. In certainembodiments, a pharmaceutical composition described herein including aco-crystal described herein and an additional pharmaceutical agent showsa synergistic effect that is absent in a pharmaceutical compositionincluding one of the co-crystal and the additional pharmaceutical agent,but not both.

The co-crystal or composition can be administered concurrently with,prior to, or subsequent to one or more additional pharmaceutical agents,which may be useful as, e.g., combination therapies in treating and/orreducing the risk for a neuropsychiatric disorder in a subject.Pharmaceutical agents include therapeutically active agents.Pharmaceutical agents also include prophylactically active agents.Pharmaceutical agents include small organic molecules such as drugcompounds (e.g., compounds approved for human or veterinary use by theU.S. Food and Drug Administration as provided in the Code of FederalRegulations (CFR)), peptides, proteins, carbohydrates, monosaccharides,oligosaccharides, polysaccharides, nucleoproteins, mucoproteins,lipoproteins, synthetic polypeptides or proteins, antibodies, smallmolecules linked to proteins such as antibodies, glycoproteins,steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides,oligonucleotides, antisense oligonucleotides, lipids, hormones,vitamins, and cells. In certain embodiments, the additionalpharmaceutical agent is a pharmaceutical agent useful in treating and/orreducing the risk for a neuropsychiatric disorder in a subject. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent approved by a regulatory agency (e.g., the US FDA)for treating and/or reducing the risk for a neuropsychiatric disorder ina subject. Each additional pharmaceutical agent may be administered at adose and/or on a time schedule determined for that pharmaceutical agent.The additional pharmaceutical agents may also be administered togetherwith each other and/or with the co-crystal or composition describedherein in a single dose or administered separately in different doses.The particular combination to employ in a regimen will take into accountcompatibility of the co-crystal described herein with the additionalpharmaceutical agent(s) and/or the desired therapeutic and/orprophylactic effect to be achieved. In general, it is expected that theadditional pharmaceutical agent(s) in combination be utilized at levelsthat do not exceed the levels at which they are utilized individually.In some embodiments, the levels utilized in combination will be lowerthan those utilized individually.

In certain embodiments, the additional pharmaceutical agent is an agentfor treating a neuropsychiatric disorder. In certain embodiments, theco-crystals described herein or pharmaceutical compositions can beadministered in combination with a therapy for treating aneuropsychiatric disorder.

Without further elaboration, it is believed that one skilled in the artcan, based on the above description, utilize the present invention toits fullest extent. The following specific embodiments are, therefore,to be construed as merely illustrative, and not limitative of theremainder of the disclosure in any way whatsoever. All publicationscited herein are incorporated by reference for the purposes or subjectmatter referenced herein.

EXAMPLES

In order that the present disclosure may be more fully understood, thefollowing examples are set forth. The synthetic and biological examplesdescribed in this application are offered to illustrate the co-crystals,compounds, compositions, and methods provided herein and are not to beconstrued in any way as limiting their scope.

The following are exemplary methods of preparing co-crystals describedherein.

Example 1 Preparation of Lithium Benzoate:Sorbic Acid (1:2 Co-Crystal)via Heating in Saturated Solution

To the round bottom flask were added lithium benzoate (5.0 g, 39.1 mmol)and sorbic acid (4.4 g, 39.1 mmol, followed by the addition of methanol(80 ml). The mixture was stirred at 65° C. till all solids were fullydissolved. The temperature was raised to 75° C. and methanol was slowlydistilled off for the lithium benzoate:sorbic acid 1:2 co-crystal toform. The distillation was continued until 25 ml of methanol remained inthe flask. The co-crystal formed was then filtered and dried undervacuum at room temperature overnight to render 3.0 g of the desiredco-crystal.

The co-crystal obtained from Example 1 was analyzed by ¹H-NMR, powderX-ray diffraction, thermoanalysis, and IR analyses as described herein.

Thermogravimetric Analysis (TGA): TGA data were measured by Pyris 1 TGA(Perkin Elmer) with platinum crucibles with the heating rate of 10°C./min, between 50° C.-700° C.

Differential Scanning calorimetry: The melting point of the co-crystalwas determined using the differential scanning calorimeter (DSC) method.The DSC data were measured by DSC 8000 (Perkin Elmer) with T-zeroaluminum low-mass pan at the heating rate of 10° C./min and the heatingrange of 50° C.-450° C.

X-ray Powder Diffractometry: X-ray diffraction patterns were obtained onD8 ADVANCE (Bruker AXS Gmbh, Germany). Samples were scanned incontinuous mode from 0-45° (2θ) with step size of 0.02° on a spinningstage at 40 kV and 40 mA with Cu Kα radiation. The incident beam pathwas equipped with a 0.2 mm divergence slit and 0.02 mm air scatteringscreen. The diffracted beam was equipped with Ni-filter. Detection wasaccomplished with a Lynxeye detector (Bruker AXS).

¹H-NMR: ¹H Nuclear magnetic resonance (NMR) analysis was performed onBruker Fourier 400 (Bruker) in deuterated solvents such as d-methanol at25° C. The NMR for FIGS. 1, 5, and 10 was performed in d-methanol at 25°C.

IR: Infrared (IR) analysis was conducted on Spectrum 100 FT-IRSpectrometer (Perkin Elmer) by the KBr pellet method.

The ¹H-NMR, powder X-ray diffraction, thermoanalysis, and IR analysesresults of the co-crystal obtained by the method described in Example 1are shown in FIGS. 1-4, respectively.

Example 2 Preparation of Lithium Benzoate:Trans-Cinnamic Acid (1:1Co-Crystal) via Heating in Saturated Solution

To a mixture of lithium benzoate (5.0 g, 39.1 mmol) and trans-cinnamicacid (5.8 g, 39.1 mmol) in the round-bottom flask was added 180 mL ofmethanol. The slurry was stirred at 65° C. until all solids weredissolved. The mixture was heated to 75° C. to reduce the volumemethanol to around 125 ml by slow evaporation for the lithiumbenzoate:trans-cinnamic acid co-crystal to generate in the solution. Thecrystals were collected by filtration and dried under vacuum to give 4.1g of the desired co-crystal. The ¹H-NMR, powder X-ray diffraction,thermoanalysis, and IR analyses results of the co-crystal obtained bythe method described in Example 1 are shown in FIGS. 5-9, respectively.

Example 3 Preparation of Lithium Benzoate:Nicotinic Acid (1:1Co-Crystal) via Heating in Saturated Solution

To a mixture of lithium benzoate (5.0 g, 39.1 mmol) and nicotinic acid(4.8 g, 39.1 mmol) was added 170 mL of methanol. The mixture was stirredat 65° C. to dissolve all solid powders. The temperature was raised to75° C. to slowly evaporate methanol for the co-crystal to begin to formin the solution. The evaporation was halted when 120 mL of methanolremained. The crystals formed were filtered and dried under vacuum atroom temperature overnight to afford 3.6 g of the co-crystal. The¹H-NMR, powder X-ray diffraction, thermoanalysis, and IR analysesresults of the co-crystal obtained by the method described in Example 1are shown in FIGS. 10-14, respectively.

EQUIVALENTS AND SCOPE

In the claims, articles such as “a,” “an,” and “the” may mean one ormore than one unless indicated to the contrary or otherwise evident fromthe context. Claims or descriptions that include “or” between one ormore members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should be understood that, in general, where the invention, oraspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A co-crystal of a lithium benzoate compound and a co-former, whereinthe co-former is selected from a compound of Formula (I):

in which L is alkyl, carbocyclyl, C═C, C═C—C═C, C≡C, or absent; A isalkyl, carbocyclyl, aryl, or heteroaryl; and X is O or N—B, B being H,alkyl, carbocyclyl, aryl, or heteroaryl.
 2. The co-crystal of claim 1,wherein the lithium benzoate compound and the co-former exist in theco-crystal in a molecular ratio ranging from 1:10 to 10:1.
 3. Theco-crystal of claim 1, wherein L is C═C or C═C—C═C, and A is C₁-C₆alkyl, aryl, or heteroaryl.
 4. The co-crystal of claim 3, wherein L isC═C—C═C, A is methyl, and X is O.
 5. The co-crystal of claim 4, whereinthe lithium benzoate compound and the co-former exist in the co-crystalin a molecular ratio of 1:2.
 6. The co-crystal of claim 5, wherein theco-crystal has a powder X-ray diffraction pattern substantially asdepicted in FIG.
 2. 7. The co-crystal of claim 3, wherein L is C═C, A isphenyl, and X is O.
 8. The co-crystal of claim 7, wherein the lithiumbenzoate compound and the co-former exist in the co-crystal in themolecular ratio of 1:1.
 9. The co-crystal of claim 8, wherein theco-crystal has a powder X-ray diffraction pattern substantially asdepicted in FIG. 6, and an endothermic peak corresponding to the meltingpoint of about 188° C.
 10. The co-crystal of claim 3, wherein L isabsent, A is pyridyl, and X is O.
 11. The co-crystal of claim 10,wherein the lithium benzoate compound and the co-former exist in theco-crystal in the molecular ratio of 1:1.
 12. The co-crystal of claim11, wherein the co-crystal has a powder X-ray diffraction patternsubstantially as depicted in FIG. 11, and an endothermic peakcorresponding to the melting point of about 161° C.
 13. A composition,comprising an effective amount of a co-crystal of claim 1 and a carrier.14. The composition of claim 13, wherein the composition is apharmaceutical composition, a nutraceutical composition, a health food,or a medical food.
 15. A method of treating or reducing the risk for aneuropsychiatric disorder in a subject, the method comprisingadministering to the subject a therapeutically effective amount of theco-crystal of claim
 1. 16. The method of claim 15, wherein theneuropsychiatric disorder is selected from the group consisting ofschizophrenia, psychotic disorders, Alzheimer's disease, dementia, mildcognitive impairment, benign forgetfulness, closed head injury, autisticspectrum disorders, Asperger's disorder, attention deficit hyperactivitydisorders, obsessive compulsive disorder, tic disorders, childhoodlearning disorders, premenstrual syndrome, depression, bipolardisorders, anxiety disorders, post-traumatic stress disorder, chronicpain, eating disorders, addiction disorders, personality disorders,Parkinson's disorder, Huntington's disorder and amyotrophic lateralsclerosis.
 17. A method for preparing a co-crystal of claim 1, themethod comprising: (i) mixing the lithium benzoate compound and theco-former in a solvent at a temperature of about 40-110° C. to form asaturated solution, wherein the lithium benzoate compound and theco-former are at a molar ratio of 1:10 to 10:1; (ii) heating andstirring the solution at a temperature of about 70-150° C. to allowformation of the co-crystal; and collecting the co-crystal formed in(ii).
 18. The method of claim 17, wherein step (i) is performed byadding the solvent in a dropwise manner into the lithium benzoatecompound and co-former and stirring the mixture thus formed to allowdissolution of the lithium benzoate compound and co-former in thesolvent.
 19. A method for preparing a co-crystal of claim 1, the methodcomprising: providing a co-crystal of claim 1, (i) dissolving theco-crystal in a solvent at a temperature ranging from about 35-110° C.to form a solution; (ii) stirring the solution at a temperature of about40-110° C. for a first period to allow formation of the co-crystal;wherein the first period is about 1-10 days; and collecting theco-crystal.
 20. The method of claim 19, further comprising, followingstep (iii), stirring the solution at a temperature of about 40-110° C.for a second period, wherein the second period is about 1-10 days.